The ability to detect and interpret communicative vocalizations is fundamental to human interaction. Identifying brain circuits and mechanisms that support vocal perception is essential for treatment of the broad array of pathologies that affect speech comprehension, such as aphasic stroke, autism and developmental dyslexia. Most of these conditions involve damage or dysfunction in the auditory cortex, indicating that this structure plays an essential role in vocal perception. Disappointingly, the cortical circuit mechanisms that underlie the perception of communicative vocalizations and the role of auditory cortex in selecting appropriate behavioral responses remain enigmatic. The goal of this proposal is to integrate optogenetic, electrophysiological and behavioral methods to resolve the synaptic properties of cortical circuits that enable vocal recognition and to test the role of the auditory cortex in mediating auditory-guided behavior. This goal requires a model animal that relies on vocal communication, is suitable for high-resolution electrophysiological analysis of neural circuitry, and is amenable to genetic tools for manipulating brain activity. Mice are highly social mammals that use vocalizations to communicate, and are accessible to cutting edge techniques for precisely dissecting the synaptic organization and function of the auditory cortex. Female mice are selectively drawn towards cries of isolated pups, simplifying assessment of vocal perception and its relation to neural activity. Moreover, the mouse auditory cortex contains a region (UF) specialized for the detection of sounds in the acoustic frequency range of pup cries, thus narrowing the search for vocal perception circuitry. Despite these critical advantages, little is known about the functional synaptic properties of the mouse auditory cortex and how these properties serve vocal recognition. Our proposal takes advantage of newly created lines of genetically modified mice that express a light-sensitive ion channel in restricted subsets of cortical neurons. Expression of this channel protein allows one to precisely manipulate neural activity, and thus to ascertain detailed synaptic connections between UF and surrounding auditory cortical regions that we hypothesize may support vocal recognition. Furthermore, we will functionally assess whether activity in the UF circuit is necessary and sufficient for releasing vocalization-evoked locomotor behavior in female mice. This approach to examining the mechanisms of vocal perception in the mouse model offers several crucial benefits that extend well beyond the scope of the biology of vocal communication in mice, and are directly relevant to the concept of the R21 mechanism specifically and NIH's health mission generally. First, the proposal features the development of innovative approaches to probing cortical circuitry that will be readily applicable to a wide range of systems. Second, because the mouse cortex shares much of its cell type diversity and basic synaptic microcircuitry with the human cortex, our results are almost certain to reveal general principles of auditory spectral integration that will directly enrich our understanding of human auditory cortical function. Finally, development of a mouse model of social vocal communication will open new avenues of research for our group as well as many others, allowing analysis of how genetic disorders that alter cortical synaptic architecture interfere with social cognition and communication. Identifying the neural mechanisms that support vocal perception is germane to treatment of pathologies that affect speech comprehension, such as aphasic stroke, autism and developmental dyslexia. The auditory cortex plays an essential role in vocal perception, but the cortical mechanisms that underlie vocal recognition and the role of cortical circuits in auditory-guided behavior remain unresolved. Therefore, this proposal's goal is to develop and integrate genetic, electrophysiological and behavioral approaches in mice to assess how synaptic circuits in auditory cortex enable vocal recognition and to test their role in mediating auditory-guided behavior. [unreadable] [unreadable] [unreadable]